Metformin-associated hyperlactacidaemia acidosis: Diagnosis rate in standard clinical practice and its relationship with renal failure. / Acidosis con hiperlactacidemia por metformina: frecuencia de su diagnóstico en la práctica clínica habitual y relación con la insuficiencia renal.

BACKGROUND AND OBJECTIVES: Observational study on the difference between the number of cases of acidosis with hyperlactacidaemia suspected of being caused by metformin diagnosed in standard clinical practice and the incidence of this condition according to the datasheet. The study also explored the relationship between renal function and metformin-associated hyperlactacidaemia acidosis. PATIENTS: We identified cases of acidosis between 2013 and 2014 by analysing the minimum basic data set and laboratory requests. We selected patients who presented venous lactate levels >2.7 mmol/L at the time they were treated and for whom the use of outpatient metformin was confirmed. The causal relationship with metformin was independently evaluated by several researchers. The incident cases were calculated based on the number of patients who had been dispensed a drug containing metformin during the same period in the study area. RESULTS: We identified 476 cases of acidosis. Metformin was suspected of causing the condition of acidosis with hyperlactacidaemia in 20 of these cases, which represents an incidence rate of 6.57/10,000 patients. Eighty-five percent of the cases presented acute renal failure. CONCLUSIONS: The apparent incidence of acidosis with hyperlactacidaemia in patients treated with metformin is greater than that established in the datasheet (<1/10,000). The onset of metformin-associated hyperlactacidaemia acidosis is related to acute renal impairment.

Rationale and design of a randomized, double-blind, placebo controlled multicenter trial to study efficacy, security, and long term effects of intermittent repeated levosimendan administration in patients with advanced heart failure: LAICA study.

BACKGROUND: Advanced heart failure (HF) is associated with high morbidity and mortality; it represents a major burden for the health system. Episodes of acute decompensation requiring frequent and prolonged hospitalizations account for most HF-related expenditure. Inotropic drugs are frequently used during hospitalization, but rarely in out-patients. The LAICA clinical trial aims to evaluate the effectiveness and safety of monthly levosimendan infusion in patients with advanced HF to reduce the incidence of hospital admissions for acute HF decompensation. METHODS: The LAICA study is a multicenter, prospective, randomized, double-blind, placebo-controlled, parallel group trial. It aims to recruit 213 out-patients, randomized to receive either a 24-h infusion of levosimendan at 0.1 µg/kg/min dose, without a loading dose, every 30 days, or placebo. RESULTS: The main objective is to assess the incidence of admission for acute HF worsening during 12 months. Secondarily, the trial will assess the effect of intermittent levosimendan on other variables, including the time in days from randomization to first admission for acute HF worsening, mortality and serious adverse events. CONCLUSIONS: The LAICA trial results could allow confirmation of the usefulness of intermittent levosimendan infusion in reducing the rate of hospitalization for HF worsening in advanced HF outpatients.

[Emergent drugs (II): the Pharming phenomenon]. / Drogas emergentes (II): el pharming.

The use of medicines, with or without medical prescription, for recreational ends by the young population has received little attention from doctors. In the USA, one in five adolescents has used medicines for recreational purposes, and consultations in Emergency Departments for medicine abuse have exceeded those for illegal drugs. Although few data are available in Spain, such consumption is situated between 3.1 and 8.6% according to surveys. The medicines most used are dextromethorphan and methylphenidate. The former, on sale without prescription, presents a varied symptomatology, dosage and dependent metabolic action, ranging from euphoria to hallucinations. Methylphenidate, taken orally, nasally or intravenously, is used as a stimulant in substitution for cocaine and is one of the medicines most diverted onto the illicit market at the world level. In principle, other substances like modafinil and propofol present a limited incidence of non-medical use, but they have a probable abuse potential that should be borne in mind, above all in the health context. Finally, opiates like fentanyl, oxycodone and buprenorphine, with new pharmaceutical presentations, have recently become generalized in the therapeutic arsenal of many medical specialities; they are giving rise to phenomena of abuse, dependence and diversion towards the illicit market. Demands for detoxification treatment, their mixture with illegal substances, and cases of death should alert us to the abuse of these medicines.

Paediatric adverse drug reactions reported to the Spanish Pharmacovigilance System from 2004 to 2009.

PURPOSE: This study was conducted to evaluate relevant new information about ADRs reported in the Spanish paediatric population over a 6-year period. METHODS: Adverse drug reactions (ADRs) for individuals aged 0-17 years reported to the Spanish Pharmacovigilance System from 2004 to 2009 were analysed with respect to time, age and sex, category of ADR [System Organ Class (SOC)], seriousness, suspected medicines [level 2 of the Anatomical Therapeutic Chemical (ATC) Classification System] and type of reporter. RESULTS: In total, 4,279 ADR reports corresponding to 8,196 ADRs were analysed, approximately two ADRs per report. The rate of paediatric ADR reports in 2009 was 165 per million, of which nearly half (46 %) were for children (age group 2-11 years). Similar total numbers of ADRs were reported for boys and girls. The most frequent ADRs reported were from the following SOCs: general disorders and administration site conditions (34 %); skin and subcutaneous tissue disorders (15 %); nervous system disorders (14 %). Reports encompassed medicines from various ATC groups: vaccines and anti-infectives for systemic use (67 %); nervous system (9 %); respiratory system (9 %). On average, 37 % of ADRs were classified as serious. There were 33 fatal ADRs, and 35 % of the paediatric population associated with the ADR notifications required hospitalization or extended hospital stay. CONCLUSIONS: In Spain, ADR reporting rate in the paediatric population has increased since 2004. The proportion of suspected ADR reports related to vaccines was predominant, which highlights the important role played by nurses. ADR notification of congenital malformations in newborn infants highlights the need for joint action between the Spanish System of Pharmacovigilance of Medicines for Human Use (SEFV-H) and paediatricians, obstetricians and gynaecologists. The publication of safety reports by regulatory agencies is determinant for the increased number of ADR notifications.

Pharmacokinetics of once- versus twice-daily tacrolimus formulations in kidney transplant patients receiving expanded criteria deceased donor organs: a single-center, randomized study.

BACKGROUND: Noncompliance to immunosuppressive treatment is 1 of the risk factors for kidney graft loss. The once-daily, prolonged-release tacrolimus formulation may improve treatment adherence. We sought to compare the pharmacokinetics of both tacrolimus formulations in older de novo recipients of a cadaveric renal transplant from an expanded-criteria donor. PATIENTS AND METHODS: This randomized study included 27 patients (14 on once daily prolonged-release formulation [QD] and 13, on the twice-daily formulation [BID]), who were treated with 0.1 mg/kg per day of tacrolimus (target blood level, 5-8 ng/mL) mycophenolate mofetil prednisone and basiliximab induction. RESULTS: At 24 hours, in combination with the blood levels were 4.70±2.50 versus 4.70±3.04 ng/mL (P=NS). There were no significant differences in the AUC0-24 of tacrolimus (QD/BID) at 3 days (300.8±60.15 vs 287.7±125.78 ng.h/mL) or 21 days (303.05±99.79 vs 275.26±75.37 ng.h/mL), nor in blood levels (ng/mL) at 1 month (8.76±2.46 vs 8.8±1.89), 3 months (7.30±1.72 vs 8.80±1.89) and 6 months (7.19±1.89 vs 6.60±1.71). At 3 days, there was a strong correlation between AUC0-24 and Cmin both for tacrolimus QD (r=.872) and BID (r = 1.0). The incidences of acute rejection episodes were: 0% versus 16.6%; graft survivals, 100% versus 92.3% (P=NS); and patient survivals, both 100%. CONCLUSION: For older de novo recipients of kidneys from expanded criteria donors tacrolimus QD is comparable to the same dose in the BID formulation with similar at least short-term transplant outcomes.